Human papillomavirus type 6 causes the most prevalent viral sexually transmitted disease, condyloma acuminata (genital warts). Little is known of the mechanism of HPV 6-mediated pathogenicity. Low level viral gene expression is detected in the undifferentiated keratinocytes; expression significantly increases in the differentiated keratinocytes. We have detected a silencer in the regulatory region of the HPV 6 genome which down-regulates expression from the SV40 early promoter in HeLa cells. We propose that interactions with this silencer contribute to the change in viral gene expression detected as cells differentiate. Experiments are designed to test this hypothesis. The silencer element, and its cognate protein, will be defined in HeLa cells using a combination of deletional analysis and analysis of naturally arising variants. Experiments will be expanded to analyze the effect of the silencer on a homologous promoter (HPV 6 E6 promoter) in addition to the heterologous promoter (SV40 early promoter). Functional assays will be used and DNA:protein interactions will be characterized. The activity of the silencer will then be determined in basal (undifferentiated) keratinocytes and in differentiated keratinocytes. These experiments will impact on our understanding of the dynamics of the HPV 6: keratinocyte interaction that determine the outcome of infection, a condyloma. The analysis of naturally arising variants, isolated from women presenting at a Sexually Transmitted Disease Clinic, a Gynecology Clinic, and an Obstetrics Clinic, will also elucidate the extent of variability within this region of the genome. This will indicate whether analysis of this region might provide a useful epidemiological tool and whether particular variants correlate with prognosis.